World Health Organization

World Health Organization
Pharmaceutical Development 14 April, 2017 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

Pharmaceutical Development
World Health Organization Pharmaceutical Development 14 April, 2017 Stability testing of Finished Pharmaceutical Products (FPPs) Presenter: Susan Walters Fax: (61) ( is preferred)

Stability testing of FPPs
World Health Organization Stability testing of FPPs 14 April, 2017 Outline of presentation We will: Review relevant guidelines Define the objectives of stability testing Outline the design & conduct of stability studies for finished products Determine a shelf life based on study results Discuss what to include in reports of stability studies

Objectives of stability testing: What is the purpose?
World Health Organization 14 April, 2017 Objectives of stability testing: What is the purpose? "…… to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity & light, & enables recommended storage conditions, re-test periods & shelf lives to be established” (ICH) 2003

Variables that might affect the stability of a given API & dosage form
World Health Organization Variables that might affect the stability of a given API & dosage form 14 April, 2017 Formulation Packaging Site and method of manufacture API Finished product Batch size Batch to batch variability The importance of process validation & quality risk management Container labelling Changes to product

14 April, 2017 Stability testing Development studies Characterise compatibility with common excipients Characterise stability profile of API Eg susceptibility to acid, base, light, oxygen etc…… Characterise stability profile of early formulations Especially susceptibility to heat, humidity & light Confirmatory studies Long term & accelerated studies on the product as it is to be registered In practice design is now largely dictated by ICH guidelines

14 April, 2017 What does a regulator want to see demonstrated in the registration dataset? The product maintains relevant quality characteristics within the acceptable range: In proposed registration formulation & container/closure system For whole of shelf life At permitted extremes of storage Over all batches When manufactured at all registered sites (API & finished product) After any changes

Relevant guidelines 14 April, 2017 Many countries have their own guidelines concerning stability testing & other registration topics But if a manufacturer wishes to market a product in several countries, it is simpler to use one of the international guidelines, such as those of WHO & ICH So how widely are WHO & ICH guidelines accepted? Most countries will accept data generated according to ICH guidelines Many countries will accept data generated according to WHO guidelines, & especially when the product in question has been prequalified by WHO But possibly not ICH countries Whilst ICH guidelines are more detailed than those of WHO, there are few ‘in-principle’ differences, except in relation to testing conditions for hot & humid climates

ICH stability guidelines - 1
World Health Organization ICH stability guidelines - 1 14 April, 2017 Q1A(R2) Stability Testing of New Drug Substances & Products Q1B Stability Testing : Photostability Testing of New Drug Substances & Products Q1C Stability Testing for New Dosage Forms Available via html

World Health Organization ICH stability guidelines - 2 14 April, 2017 Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E Evaluation of Stability Data Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV Withdrawn Also available via html

World Health Organization ICH stability guidelines - 3 14 April, 2017 Remember that these have been adopted in the European Union, the United States, and Japan Technically ICH guidelines apply only to new APIs & products made from them. But most regulators give ICH guidelines considerable weight when deciding requirements for non-new APIs.

WHO stability guidelines - 1
World Health Organization WHO stability guidelines - 1 14 April, 2017 “Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” WHO (1996) Available via Note: Applies to ‘Well established drug substances’ Applies to ‘Conventional dosage forms’ These guidelines are under revision : See

WHO stability guidelines - 2
World Health Organization WHO stability guidelines - 2 14 April, 2017 So what are the types of product to which WHO guidelines (1996) do not apply? New chemical entities (NCEs) And possibly also new dosage forms of NCEs New combinations of actives Modified release dosage forms, including Slow release products Transdermal patches Modified release injections

Stability guidelines for WHO’s Prequalification Program (PQP) - 1
World Health Organization Stability guidelines for WHO’s Prequalification Program (PQP) - 1 14 April, 2017 Stability testing: Section 3.11 of Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria & Tuberculosis Available via Are consistent with ICH guidelines There are extensive cross references to ICH guidelines Effectively the PQP text is a practical interpretation of ICH guidelines

Stability guidelines for WHO’s PQP - 2
World Health Organization Stability guidelines for WHO’s PQP - 2 14 April, 2017 “Extension of the WHO list of stable (not easily degradable ARV) APIs” WHO (2006) Also available via Read this carefully. It describes circumstances in which a tentative 2-year shelf life may be allocated to certain APIs & FPPs, subject to a number of strict conditions.

Stability report formats for WHO’s PQP
World Health Organization Stability report formats for WHO’s PQP 14 April, 2017 Annex 3: Model stability report of API Annex 4: Model stability report of capsules/tablets Also available via

Terminology – adapted from ICH 2000 (1)
World Health Organization 14 April, 2017 Terminology – adapted from ICH 2000 (1) Production batch: A batch manufactured at production scale using production equipment & in a production facility as specified in the registration application Pilot scale batch: A batch manufactured by a procedure “fully representative of & simulating” full production scale. For tablets & capsules, this means 100,000 units or 1/10th of production scale, whichever is the larger

World Health Organization Terminology – adapted from ICH 2000 (2) 14 April, 2017 Re-test period: API The period of time for which the API remains within specification when stored under the recommended conditions in the proposed bulk storage container “After this period, the batch should be retested for compliance with specifications & then used immediately” [if in compliance]

World Health Organization Terminology – adapted from ICH 2000 (3) 14 April, 2017 Accelerated testing Studies designed to increase the rate of chemical degradation or physical change by means of exaggerated storage conditions Intermediate testing Studies at 30degC/60%RH, intended for extrapolation to long term storage at 25degC [provided that 25degC is appropriate for the market in question] Stress testing API: Studies which elucidate intrinsic stab of API. Normally during development. Normally more stressful than ‘accelerated’ testing. Finished product: Studies of effect of ‘severe’ conditions. Eg freeze/thaw cycling for suspensions & emulsions, low humidity for aqueous liquids in moisture-permeable containers. Accelerated testing: Intended to allow extrapolation of conditions at max recd storage conditions Or to “evaluate effect of short term excursions outside label storage conditions” Intermediate testing: Relevant if want to label product as “Store below 25degC”. Stress testing: For API, means devt studies Examples of stress tests for finished product might be cycling temps (eg emulsions, creams), refrigeration for liquids which are or might be stored at low temp. Not sure what is referred to for mdis – FDA mentions possibility of testing at 25degC/75%RH for 1/3 of shelf life if moisture resistant packaging needed (?dpis).

World Health Organization Terminology – adapted from ICH 2000 (4) 14 April, 2017 In-use stability testing: Establishes the “period of time during which a multidose product can be used whilst retaining quality within an accepted specification once the container is opened” ICH 2000 For example: liquids that are reconstituted prior to use effervescent tablets in a moisture-proof container (eg Al screw-cap tube) ophthalmic products (especially with respect to preservative efficacy)

World Health Organization 14 April, 2017 Terminology – adapted from ICH 2000 (5) Climatic zones: Partition of the world into three temperature classes based on kinetic averaging of monthly temperatures, & subdivision of the hottest class into predominantly wet or predominantly dry Zones (Futscher & Schumacher 1972): I Temperate (21oC/45%RH) II Subtropical (25oC/60%RH with possibly high RH) III Hot & dry (30oC/35%RH) IV Hot & wet (30oC/70%RH) The temperatures above are kinetic averages Zones originally proposed by Futscher & Schumacher Grimm subsequently elaborated mean annual %RH and kinetic temps for world regions based on meteorological data.

Extract of WHO Technical Report Series Expert committee on specifications for pharmaceutical preparations (2006): Quality assurance: Stability testing conditions 14 April, 2017 “The Secretariat reminded the Committee that the WHO guidelines had been revised in the light of harmonization efforts in collaboration with ICH. Subsequently focus had been placed within regional harmonization initiatives on the recommendations for hot and humid conditions (referred to as Zone IV). After extensive discussion the Committee reached consensus that the WHO stability guidelines be amended to reflect conditions for Zone IV as follows: — Zone IVa (30 degrees Celsius and 65% relative humidity); and — Zone IVb (30 degrees Celsius and 75% relative humidity). It was agreed that each individual Member State within the former Zone IV would need to indicate whether its territory should be classified as Zone IVa or IVb.”

Consequently… 14 April, 2017 Each nation within zone IV must now decide whether to adopt a stability test condition of 30oC & 65%RH, or 30oC & 75%RH ASEAN nations & Brazil have adopted 30oC & 75%RH

World Health Organization 14 April, 2017 Terminology – adapted from ICH 2000 (6) Reduced study designs: Bracketing A design in which only the extremes are tested at all time points, eg strength, pack size, container fill Matrixing Designs in which a selected subset of samples is tested, eg different strengths, container/closure systems, batches Reduced study designs: ICH emphasises: Bracketing not applicable to APIs Matrixing has “limited utility” Are risks involved in conducting reduced study designs, and must justify use in each case In general, I suspect that ICH is implying (but not actually stating) that bracketing and matrixing is appropriate when there is a reasonable expectation that there will be no significant change. Bracketing: Assumes that intermediate conditions (ie those not tested) are intermediate in all respects. Eg if test different cap strengths, that all strengths are made from same granulation with different compression weights. Matrixing: I would add that can matrix temps, but ICH does not specifically mention that so might not get through TGA Fff

Example of a bracketing design
World Health Organization 14 April, 2017 This is an example of a bracketing design. The table was taken from the current ICH draft entitled “Bracketing and matrixing designs for stability testing of new drug substances and products”. In this design, 12 sets of tests are conducted at each time point instead of 15. Intermediate strength does not have to be same formulation, so long as is all ingredients in the intermediate strength are intermediate in proportion between upper and lower strengths. As we said earlier today, these designs do carry a risk in that if one element of the design shows instability, may be left with a very incomplete dataset. For example if the 50mg strength showed instability, have no acceptable data on the 75mg strength either. I have seen cases of instability of a strength at one end of a range, even with tablets. So prudence would suggest would not undertake this design unless already have some data on these or related formulations. T = Sample is tested

Example of a matrixing design “One half reduction”
World Health Organization 14 April, 2017 A number of matrix designs are tabulated in the ICH guideline, of which this is one. ICH describes this as a “Matrixing design on time points for a product with two strengths; One-half reduction”. Describes a product for which three batches of each strength have been put on test. Samples of every strength and batch are tested at the beginning and at the end of the study, and at the 12 months time point. At the intermediate time points, only half of the samples are tested. T = Sample is tested

When might bracketing & matrixing be appropriate? (NB The following is not from ICH ! You must argue the case!) World Health Organization 14 April, 2017 Container size? Batch size? Formulation of coating? With varying amounts of an excipient (eg starch, Mg stearate)? EXERCISE What are some other situations in which bracketing and matrixing may be appropriate?

The risk associated with bracketing & matrixing
World Health Organization 14 April, 2017 If the results are not what you expected, you may have insufficient to propose an intermediate shelf life Would be risky to use bracketing & matrixing if you did not have a good idea as to what the product’s stability will be Consequently: Bracketing & matrixing designs are used mainly for confirmatory studies EXERCISE What are some other situations in which bracketing and matrixing may be appropriate?

14 April, 2017 ICH minimum dataset at submission - 1 If you think you have seen this table before, you have. It is identical to the one for APIs.

14 April, 2017 ICH minimum dataset at submission - 2 FPPs packaged in impermeable containers need not be stored under controlled humidity conditions There are different minimum conditions for: Liquid products packaged in semi-permeable containers [relating to potential loss of solvent] Products intended for storage in a refrigerator, freezer or deep-freeze If you think you have seen this table before, you have. It is identical to the one for APIs.

Classes of degradation
World Health Organization Classes of degradation 14 April, 2017 Chemical Physical Microbiological

Chemical degradation 14 April, 2017 Has been dealt with by Dr Elder

Physical degradation (≡ physicochemical degradation)
World Health Organization Physical degradation (≡ physicochemical degradation) 14 April, 2017 Physical properties can change too! Important attributes vary with dosage form Bottom line is relevance to quality, safety & efficacy Examples for liquid formulations: Appearance, colour, odour, pH, clarity (solutions) and freedom from visible particulate contamination, size range of particulate contamination (large volume parenterals), particle size distribution (suspensions), micelle size distribution (micellar solutions), resuspendability (suspensions), viscosity, moisture content (powders for reconstitution), phase separation (emulsions) See other examples at

Other forms of physical deterioration may include:
World Health Organization Other forms of physical deterioration may include: 14 April, 2017 Leaching Absorption (into container walls) Adsorption (on to container walls) Volatilisation (eg sertraline base, glyceryl trinitrate) Altered particle size distribution Loss of higher order molecular structure (normally only for biological medicines) Denaturation Aggregation

Minimising physical deterioration
World Health Organization 14 April, 2017 Minimising physical deterioration Some examples: When prone to adsorption on to, or absorption into, packaging materials, use resistant packaging materials, such as good quality glass When prone to volatilisation: Use a non-volatile salt (if possible) Use packaging materials that are resistant to vapour transfer When prone to altered particle size in suspensions: Formulate a continuous phase in which the active is less soluble

Microbiological deterioration
World Health Organization 14 April, 2017 Microbiological deterioration Proliferation of microbes in non-sterile products Consequences may include: Infection of the patient Formation of endotoxins (≡ pyrogens) Foul odour Formation of gas Change in colour Cloudiness Hydrolysis

Minimising microbiological deterioration of non-sterile products
World Health Organization 14 April, 2017 Minimising microbiological deterioration of non-sterile products Control the microbial load of API & excipients Validate & monitor manufacturing conditions Include antimicrobial preservatives in formulations NB Normally only bacteriostatic & not bactericidal

Appropriate tests for stability studies - 1
World Health Organization Appropriate tests for stability studies - 1 14 April, 2017 Normally test same attributes as for routine QC May use other methodology for stability testing (avoid for dissolution rate) but must be validated Avoid changing methodology mid-study (unless correcting a clear deficiency)

Appropriate tests for stability studies - 2
World Health Organization Appropriate tests for stability studies - 2 14 April, 2017 Quantitate degradation products if possible, even if the assay is specific for the API But can be difficult to quantitate impurities if there are no reference standards & relative response factors are unknown → semiquantitative estimates Regulatory authorities usually expect an approximate mass balance Appropriate physical tests vary with dosage form. Remember to conduct preservative efficacy tests too, in addition to assay of any antimicrobial preservative

For all stability studies
World Health Organization For all stability studies 14 April, 2017 Validate the analytical methodology! See relevant guidelines, especially: Validation of analytical procedures: Terminology ICH Q2B 1994 Validation of analytical procedures: Methodology ICH Q2B 1996 Use stability-indicating assays

Dissolution rate World Health Organization 14 April, 2017 Avoid using a method different to that in routine QC Most regulatory authorities, including PQP, prefer dissolution profiles rather than single time points during stability testing. Better ability to detect trends. Avoid using a method different to that in routine QC (less critical for assay during dissolution test) Very difficult to interpret results in terms of compliance with specifications over time, if for example the rotation speed is different to that in routine QC TGA has preference for dissolution profiles rather than single time points, even for IR products Certainly provides more information than single point tests Is a requirement for prolonged release products

Frequency of testing during a stability study - ICH
World Health Organization 14 April, 2017 Frequency of testing during a stability study - ICH “For long term studies, frequency of testing should be sufficient to establish the stability profile of the pharmaceutical product” “For products with a proposed shelf life of at least 12 months, the frequency of testing in the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, & annually thereafter throughout the proposed shelf life. Other frequencies are suggested for accelerated & intermediate storage conditions. ICH 2003 ICH requirements are the minimum. More frequent testing, especially in early stages, allows earlier detection of a problem. See the sensible TGA comment (from 1970s and in 1994 AGRD)

Some notes concerning reporting (1)
World Health Organization Some notes concerning reporting (1) 14 April, 2017 It is rarely appropriate to cite only average results For the benefit of the manufacturer & the DRA Dissolution results on individual tablets (not only mean results) It’s certainly OK to cite mean & derived results as well Assay results should be reported as absolute values And not only as values normalised for initial results, ie % of initial Test methods must be recorded with the study report By the time that stability studies are conducted on finished product, is possible that more than one method has been used Is rarely appropriate to cite only average results hides information For benefit of your company & the DRA Eg dissolution results on 6 tablets By all means cite mean & derived results too (eg std dev) Assay results should be reported as absolute values (and not only as values normalised for initial results, ie % of initial) By all means provide percent of initial as well Record test methods By the time that stability studies ar conducted on finished product, likely to be > one method that could have been used

Some notes concerning reporting (2)
World Health Organization Some notes concerning reporting (2) 14 April, 2017 Numerical results should be provided wherever possible Not just ‘complies’ If results are below the limit of quantitation, they should be reported as ‘below LQC’ or similar wording ‘Not detectable’ is acceptable provided it is defined & reasonable Results that are out of the ordinary should be discussed Product labelling should be consistent with stability data. For example: Solvents for reconstitution Recommendations for mixing of injections with other injections Give numerical results wherever possible ie not just ‘complies’ If results are below limit of quantitation, report as ‘below LQC’ or similar wording Results that are out of the ordinary: Eg discolouration of a tablet May need further investigation Pre-empt questions from regulator Avoid embarrassing qns years after the event Check product labelling for statements relevant to stability results, & ensure data have been provided - Eg Solvents for dilution (example of soluble hydrochloride that was recommended for dilution in 0.9% NaCl). On conducting the study, drug precipitated out of solution. HClde was not as soluble as manufacturer had thought – had not done calculations. Recommendations for mixing with other injections

Evaluation / Interpretation of the results
World Health Organization Evaluation / Interpretation of the results 14 April, 2017 So what’s the shelf life? Give numerical results wherever possible ie not just ‘complies’ If results are below limit of quantitation, report as ‘below LQC’ or similar wording Results that are out of the ordinary: Eg discolouration of a tablet May need further investigation Pre-empt questions from regulator Avoid embarrassing qns years after the event Check product labelling for statements relevant to stability results, & ensure data have been provided - Eg Solvents for dilution (example of soluble hydrochloride that was recommended for dilution in 0.9% NaCl). On conducting the study, drug precipitated out of solution. HClde was not as soluble as manufacturer had thought – had not done calculations. Recommendations for mixing with other injections

14 April, 2017 First point The validity of an assigned shelf life depends upon: The results of stability studies, & Whether the batches used in the stability studies accurately model those to be marketed, & Whether analytical methodology was adequately validated

14 April, 2017 Assigning a shelf life Assigning a shelf life is easier if results are available: For the full duration of the proposed shelf life At the maximum recommended storage conditions For all formulations & manufacturing methods In exactly the packaging to be registered At all sites of manufacture of finished product & API If these conditions are not met, that’s when shelf life assignment becomes difficult. There will be arguments between manufacturers & registration/prequalification authorities There will be delays in approving the product Unfortunately manufacturers are not always in the position of having exactly this information Especially generic manufacturers who may have decided to develop and register the product in the last year.

Statistical estimation of shelf life - 1
World Health Organization 14 April, 2017 Statistical estimation of shelf life - 1 “Where the data show so little degradation & so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis but only to provide a justification for the omission” ICH 2003 & PQP 2005 In other words: If it is blindingly obvious that there is minimal change in the parameter in question, is unnecessary to conduct the numerical/statistical analysis.

World Health Organization 14 April, 2017 Statistical estimation of shelf life - 2 “An approach for analyzing data of a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence interval for the mean curve intersects the acceptance criterion” ICH 2000 Most pharmaceuticals are complex systems in which kinetic equations do not apply. FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.

World Health Organization 14 April, 2017 Statistical estimation of shelf life - 3 Is there any degradation of any relevant product characteristic? If no, then shelf life assignment is straightforward based on the labelled storage conditions & the time for which testing has been conducted If yes (that is there is at least some degradation/change): Conduct a statistical analysis using a suitable software package Consider: Statistical pooling of results for multiple batches Estimation of time to degrade to expiry limits using a 95% confidence interval See the file concerning software packages NB I am not recommending any of these software packages! Conduct your own Internet search! Then evaluate cost against usefulness to your company. Most pharmaceuticals are complex systems in which kinetic equations do not apply. FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.

World Health Organization 14 April, 2017 Statistical estimation of shelf life - 4 Superimposition of a 95% confidence interval on to the regression line for stability data from Bolton 1984 NB This is an old graph & it describes a very unstable product This is a graph of assay of a product against time at a given storage condition. - Taken from FDA guideline of 1987 Shows 95% confidence interval for loss of active after least squares regression Program for calculation is on FDA website: Less reliable for deterioration of physicochemical properties, which can show non-linear changes, eg sudden deterioration such as formation of a precipitate.

What are the limitations of this statistical algorithm?
World Health Organization 14 April, 2017 What are the limitations of this statistical algorithm? It applies only to quantitative attributes Does not apply for example to colour tests, or to semiquantitative comparisons such as TLC limit tests It may be unreliable for physical attributes Such as dissolution tests & discoloration Use your judgement! Look at the slope of the curve. Does the change accelerate with time? Most pharmaceuticals are complex systems in which kinetic equations do not apply. FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.

Estimation of shelf life
World Health Organization 14 April, 2017 Estimation of shelf life “Any evaluation should consider not only the assay but also the degradation products & other appropriate attributes” ICH 2003 In other words: If evaluation of different (but relevant) attributes leads to different conclusions as to shelf life, the shortest of these shelf lives should be chosen.

Estimation of shelf life
World Health Organization 14 April, 2017 Estimation of shelf life “Where appropriate, attention should be paid to reviewing the adequacy of the mass balance & different stability & degradation performance” ICH 2003 In other words: If the loss of active is not of the same order (=approximately the same) as formation of degradation products, more investigation is needed. Note however that mass balance will always be approximate; it is rarely exact.

14 April, 2017 Factors to be taken into account when assigning a shelf life based on statistical analysis - 1 Release limits Expiry limits Results of stability studies Is there any desired safety margin? This is largely a matter for the manufacturer/supplier Safety margin? Bracketed because not a regulatory requirement A prudent manufacturer may wish to incorporate a safety margin intothe estimate of shelf life. Minimise possibility of recalls, with attendant publicity

Factors to be taken into account when assigning a shelf life based on statistical analysis - 2 14 April, 2017 A batch may be released with a result anywhere in range of release limits Consequently a prudent manufacturer will take into account the lower limit of release when estimating shelf life A batch may be released with a result anywhere in range of release limits. So starting point for that calculation is lower limit of release Applies to all tests Eg impurities, content of preservative

14 April, 2017 Combining results for several batches Poolability Most pharmaceuticals are complex systems in which kinetic equations do not apply. FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.

Poolability of multiple batches
World Health Organization 14 April, 2017 Poolability of multiple batches A statistical concept that allows the results for several batches to be combined If we estimated stability based on results for individual batches, we would have to select the shortest estimate of shelf life Pooling usually leads to a longer shelf life as compared with the results for one batch only But we must first test whether the batches can legitimately be pooled Are the batches statistically homogenous? Most pharmaceuticals are complex systems in which kinetic equations do not apply. FDA (and now ICH) addressed this by suggesting a numerical estimation of trends, ie not predicated on kinetic equations.

14 April, 2017 Testing for poolability as described by Bolton 1997 Perform statistical test for common slope Not significantly different Significantly different Use separate slope & intercept for each batch Perform statistical test for common intercept Significantly different Not significantly different Use common slope but separate intercepts Use common slope & common intercept Significance is on the basis of F tests (p>0.25) as modelled by Bolton 1997

Extrapolation beyond real-time data - 1
World Health Organization 14 April, 2017 Extrapolation beyond real-time data - 1 “Limited extrapolation of the real time data from the long term storage condition beyond the observed range to extend the shelf life can be undertaken at approval time, if justified. This justification should be based on what is known about the mechanisms of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size, existence of supporting stability data, etc. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.” ICH 2000

Extrapolation beyond real-time data - 2
World Health Organization 14 April, 2017 Extrapolation beyond real-time data - 2 “If long term data are supported by results from accelerated studies the retest period/shelf life may be extended beyond the end of the long- term studies. The proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond, the period covered by long-term data”. ” PQP 2005

References 14 April, 2017 References in your CD may be useful: Regulatory guidelines Sources of climate-controlled cabinets Software for processing stability data Most include laboratory information management for the data Defined “In-use” stability earlier today. EXERCISE: What other examples might there be of in-use stability that should be addressed in stability studies? [Possible answers: - Pdr for injn reconstituted before use - Mixing of injectable with LVPs - Heating of injectable with solid particles before use (see fluorouracil injection DBL “If a ppt has formed as a result of exposure to low temperature, redissolve by heating to 60degC accompanied by vigorous shaking. Allow to cool to body temperature prior to use”. ) Antibiotics po lqds for reconstitution by a pharmacist prior to use Issue of separate labelling after reconstitution]

Pharmaceutical Development
World Health Organization Pharmaceutical Development 14 April, 2017 Summary and conclusion Stability data submitted during the registration process should confirm that all batches of the FPP will remain of acceptable quality when stored in the marketing container, at the most extreme storage conditions permitted by container labelling & prescribing information, for the duration of the shelf life Any subsequent variations (for example to site or method of manufacture of the API or FPP) should be shown not to reduce the shelf life as defined above

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